Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening.

BACKGROUND: A next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity. METHODS: In a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT). RESULTS: Of 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred. CONCLUSIONS: The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.).

Three-Year Interval for the Multi-Target Stool DNA Test for Colorectal Cancer Screening: A Longitudinal Study.

Data supporting the clinical utility of multi-target stool DNA (mt-sDNA) at the guideline-recommended 3-year interval have not been reported.Between April 2015 and July 2016, candidates for colorectal cancer screening whose providers prescribed the mt-sDNA test were enrolled. Participants with a positive baseline test were recommended for colonoscopy and completed the study. Those with a negative baseline test were followed annually for 3 years. In year 3, the mt-sDNA test was repeated and colonoscopy was recommended independent of results. Data were analyzed using the Predictive Summary Index (PSI), a measure of the gain in certainty for dichotomous diagnostic tests (where a positive value indicates a net gain), and by comparing observed versus expected colorectal cancers and advanced precancerous lesions.Of 2,404 enrolled subjects, 2,044 (85%) had a valid baseline mt-sDNA result [284 (13.9%) positive and 1,760 (86.1%) negative]. Following participant attrition, the year 3 intention to screen cohort included 591 of 1,760 (33.6%) subjects with valid mt-sDNA and colonoscopy results, with no colorectal cancers and 63 advanced precancerous lesions [22 (34.9%) detected by mt-sDNA] and respective PSI values of 0% (P = 1) and 9.3% (P = 0.01). The observed 3-year colorectal cancer yield was lower than expected (one-sided P = 0.09), while that for advanced precancerous lesions was higher than expected (two-sided P = 0.009).Repeat mt-sDNA screening at a 3-year interval resulted in a statistically significant gain in detection of advanced precancerous lesions. Due to absence of year 3 colorectal cancers, the PSI estimate for colorectal cancer was underpowered and could not be reliably quantified. Larger studies are required to assess the colorectal cancer study findings. PREVENTION RELEVANCE: Understanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.

Optoacoustic Imaging With Decision Support for Differentiation of Benign and Malignant Breast Masses: A 15-Reader Retrospective Study.

BACKGROUND. Overlap in ultrasound features of benign and malignant breast masses yields high rates of false-positive interpretations and benign biopsy results. Optoacoustic imaging is an ultrasound-based functional imaging technique that can increase specificity. OBJECTIVE. The purpose of this study was to compare specificity at fixed sensitivity of ultrasound images alone and of fused ultrasound and optoacoustic images evaluated with machine learning-based decision support tool (DST) assistance. METHODS. This retrospective Reader-02 study included 480 patients (mean age, 49.9 years) with 480 breast masses (180 malignant, 300 benign) that had been classified as BI-RADS category 3-5 on the basis of conventional gray-scale ultrasound findings. The patients were selected by stratified random sampling from the earlier prospective 16-site Pioneer-01 study. For that study, masses were further evaluated by ultrasound alone followed by fused ultrasound and optoacoustic imaging between December 2012 and September 2015. For the current study, 15 readers independently reviewed the previously acquired images after training in optoacoustic imaging interpretation. Readers first assigned probability of malignancy (POM) on the basis of clinical history, mammographic findings, and conventional ultrasound findings. Readers then evaluated fused ultrasound and optoacoustic images, assigned scores for ultrasound and optoacoustic imaging features, and viewed a POM prediction score derived by a machine learning-based DST before issuing final POM. Individual and mean specificities at fixed sensitivity of 98% and partial AUC (pAUC) (95-100% sensitivity) were calculated. RESULTS. Averaged across all readers, specificity at fixed sensitivity of 98% was significantly higher for fused ultrasound and optoacoustic imaging with DST assistance than for ultrasound alone (47.2% vs 38.2%; p = .03). Across all readers, pAUC was higher (p < .001) for fused ultrasound and optoacoustic imaging with DST assistance (0.024 [95% CI, 0.023-0.026]) than for ultrasound alone (0.021 [95% CI, 0.019-0.022]). Better performance using fused ultrasound and optoacoustic imaging with DST assistance than using ultrasound alone was observed for 14 of 15 readers for specificity at fixed sensitivity and for 15 of 15 readers for pAUC. CONCLUSION. Fused ultrasound and optoacoustic imaging with DST assistance had significantly higher specificity at fixed sensitivity than did conventional ultrasound alone. CLINICAL IMPACT. Optoacoustic imaging, integrated with reader training and DST assistance, may help reduce the frequency of biopsy of benign breast masses.

Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study.

BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD. METHODS: Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs). RESULTS: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup. CONCLUSIONS: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.

Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening: Real-world data from a large cohort of older adults.

OBJECTIVE: To determine cross-sectional adherence with the multi-target stool DNA test used for colorectal cancer screening in a large, fully insured Medicare population. METHODS: All patients aged 65-85 with a valid multi-target stool DNA test order from 1 September 2016 to 31 August 2017 identified from the Exact Sciences Laboratories (Madison, WI; sole-source national multi-target stool DNA test provider) database were evaluated for test adherence. Cross-sectional adherence, defined as multi-target stool DNA test completion within 365 days from order date, was analyzed overall and by time to adherence, as well as by available patient (age, sex, test order date, Medicare coverage type) and provider (specialty, year of first multi-target stool DNA test order, multi-target stool DNA test order frequency, and practice location) factors. RESULTS: Among 368,494 Medicare beneficiaries (64% female), overall cross-sectional adherence was 71%. Cumulative adherence rates increased more rapidly at 30 (44%) and 60 (65%) days, followed by more gradual increases at 90 (67%), 180 (70%), and 365 (71%) days. By provider specialty, primary care clinicians represented a higher percentage of multi-target stool DNA orders than gastroenterologists (88% vs. 6%), but had a lower associated patient adherence rate (71% vs. 78%). CONCLUSIONS: In this large, national sample of Medicare insured older adults, nearly three-quarters of patients adhered with a multi-target stool DNA order for colorectal cancer screening. These real-world data should inform further clinical and population health applications, reimbursement model simulations, and guideline-endorsed colorectal cancer screening strategies adherence.

Optoacoustic Imaging and Gray-Scale US Features of Breast Cancers: Correlation with Molecular Subtypes.

Background Optoacoustic imaging can assess tumor hypoxia coregistered with US gray-scale images. The combination of optoacoustic imaging and US may have a role in distinguishing breast cancer molecular subtypes. Purpose To investigate whether optoacoustic US feature scores correlate with breast cancer molecular subtypes. Materials and Methods A total of 1972 women (with a total of 2055 breast masses) underwent prebiopsy optoacoustic US in a prospective multi-institutional study between December 2012 and September 2015. Seven readers blinded to pathologic diagnosis scored gray-scale US and optoacoustic US features of the known cancers. Optoacoustic US features within (internal) and outside of the tumor boundary (external) were scored. Immunohistochemistry findings were obtained from pathology reports. Multinomial logistic regression analysis was used to fit the US scores, adding optoacoustic US features to the model to investigate the incremental benefit of each feature. Kruskal-Wallis tests were used to analyze the relationship between molecular subtypes and feature scores. Results Among 653 invasive cancers identified in 629 women, a total of 532 cancers in 519 women, all of which had molecular markers available, were included in the analysis. Mean age ± standard deviation was 57.9 years ± 12.6. Mean total external optoacoustic US feature scores of luminal (A and B) breast cancers were higher (9.9 vs 8.8; P < .05) and total internal scores were lower (6.8 vs 7.7; P < .001) than those of triple-negative and human epidermal growth factor receptor 2-positive (HER2+) cancers. A multinomial logistic regression model showed that optoacoustic internal vessel (odds ratio [OR], 0.6; 95% confidence interval [CI]: 0.5, 0.8; P = .002), optoacoustic internal blush (OR, 0.7; 95% CI: 0.5, 0.9; P = .02), and optoacoustic internal hemoglobin (OR, 0.6; 95% CI: 0.5, 0.8; P = .001) were associated with classification of luminal versus triple-negative and HER2+ cancer subtypes. Conclusion Combined optoacoustic US imaging and gray-scale US features may help distinguish luminal breast cancers from triple-negative and human epidermal growth factor receptor 2-positive cancers. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Mann in this issue.

Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study.

BACKGROUND AND OBJECTIVES: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. RESULTS: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively. CONCLUSIONS: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

Optoacoustic imaging of the breast: correlation with histopathology and histopathologic biomarkers.

AIM: This study was conducted in order to investigate the role of gray-scale ultrasound (US) and optoacoustic imaging combined with gray-scale ultrasound (OA/US) to better differentiate between breast cancer molecular subtypes. MATERIALS AND METHODS: All 67 malignant masses included in the Maestro trial were retrospectively reviewed to compare US and OA/US feature scores and histopathological findings. Kruskal-Wallis tests were used to analyze the relationship between US and OA/US features and molecular subtypes of breast cancer. If a significant relationship was found, additional Wilcoxon-Mann-Whitney tests were used to identify the differences between molecular subtype groups. RESULTS: US sound transmission helped to differentiate between LUMA and LUMB, LUMB and TNBC, and LUMB and all other molecular subtypes combined (p values < 0.05). Regarding OA/US features, the sum of internal features helped to differentiate between TNBC and HER2-enriched subtypes (p = 0.049). Internal vessels (p = 0.025), sum of all internal features (p = 0.019), and sum of internal and external features (p = 0.028) helped to differentiate between LUMA and LUMB. All internal features, the sum of all internal features, the sum of all internal and external features, and the ratio of internal and external features helped to differentiate between LUMA and TNBC. The same features also helped to differentiate between LUMA and TNBC from other molecular subtypes (p values < 0.05). CONCLUSIONS: The use of OA/US might help radiologists to better differentiate between breast cancer molecular subtypes. Further studies need to be carried out in order to validate these results. KEY POINTS: • The combination of functional and morphologic information provided by optoacoustic imaging (OA) combined with gray-scale US helped to differentiate between breast cancer molecular subtypes.

Optoacoustic Breast Imaging: Imaging-Pathology Correlation of Optoacoustic Features in Benign and Malignant Breast Masses.

OBJECTIVE: Optoacoustic ultrasound breast imaging is a fused anatomic and functional modality that shows morphologic features, as well as hemoglobin amount and relative oxygenation within and around breast masses. The purpose of this study is to investigate the positive predictive value (PPV) of optoacoustic ultrasound features in benign and malignant masses. SUBJECTS AND METHODS: In this study, 92 masses assessed as BI-RADS category 3, 4, or 5 in 94 subjects were imaged with optoacoustic ultrasound. Each mass was scored by seven blinded independent readers according to three internal features in the tumor interior and two external features in its boundary zone and periphery. Mean and median optoacoustic ultrasound scores were compared with histologic findings for biopsied masses and nonbiopsied BI-RADS category 3 masses, which were considered benign if they were stable at 12-month follow-up. Statistical significance was analyzed using a two-sided Wilcoxon rank sum test with a 0.05 significance level. RESULTS: Mean and median optoacoustic ultrasound scores for all individual internal and external features, as well as summed scores, were higher for malignant masses than for benign masses (p < 0.0001). High external scores, indicating increased hemoglobin and deoxygenation and abnormal vessel morphologic features in the tumor boundary zone and periphery, better distinguished benign from malignant masses than did high internal scores reflecting increased hemoglobin and deoxygenation within the tumor interior. CONCLUSION: High optoacoustic ultrasound scores, particularly those based on external features in the boundary zone and periphery of breast masses, have high PPVs for malignancy and, conversely, low optoacoustic ultrasound scores have low PPV for malignancy. The functional component of optoacoustic ultrasound may help to overcome some of the limitations of morphologic overlap in the distinction of benign and malignant masses.

Downgrading and Upgrading Gray-Scale Ultrasound BI-RADS Categories of Benign and Malignant Masses With Optoacoustics: A Pilot Study.

OBJECTIVE: False-positive findings remain challenging in breast imaging. This study investigates the incremental value of optoacoustic imaging in improving BI-RADS categorization of breast masses at ultrasound. SUBJECTS AND METHODS: The study device is an optoacoustic breast imaging device with a handheld duplex laser and internal gray-scale ultrasound probe, fusing functional and morphologic information (optoacoustic ultrasound). In this prospective multisite study, breast masses assessed as BI-RADS category 3, 4A, 4B, 4C, or 5 by site radiologists underwent both gray-scale ultrasound and optoacoustic imaging with the study device. Independent reader radiologists assessed internal gray-scale ultrasound and optoacoustic ultrasound features for each mass and assigned a BI-RADS category. The percentage of mass reads for which optoacoustic ultrasound resulted in a downgrade or upgrade of BI-RADS category relative to internal gray-scale ultrasound was determined. RESULTS: Of 94 total masses, 39 were biopsy-proven malignant, 44 were biopsy-proven benign, and 11 BI-RADS category 3 masses were stable at 12-month follow-up. The sensitivity of both optoacoustic ultrasound and internal gray-scale ultrasound was 97.1%. The specificity was 44.3% for optoacoustic ultrasound and 36.4% for internal gray-scale ultrasound. Using optoacoustic ultrasound, 41.7% of benign masses or BI-RADS category 3 masses that were stable at 12-month follow-up were downgraded to BI-RADS category 2 by independent readers; 36.6% of masses assigned BI-RADS category 4A were downgraded to BI-RADS category 3 or 2, and 10.1% assigned BI-RADS category 4B were downgraded to BI-RADS category 3 or 2. Using optoacoustic ultrasound, independent readers upgraded 75.0% of the malignant masses classified as category 4A, 4B, 4C, or 5, and 49.4% of the malignant masses were classified as category 4B, 4C, or 5. CONCLUSION: Optoacoustic ultrasound resulted in BI-RADS category downgrading of benign masses and upgrading of malignant masses compared with gray-scale ultrasound.

Downgrading of Breast Masses Suspicious for Cancer by Using Optoacoustic Breast Imaging.

Purpose To assess the ability of optoacoustic (OA) ultrasonography (US) to help correctly downgrade benign masses classified as Breast Imaging Reporting and Data System (BI-RADS) 4a and 4b to BI-RADS 3 or 2. Materials and Methods OA/US technology uses laser light to detect relative amounts of oxygenated and deoxygenated hemoglobin in and around suspicious breast masses. In this prospective, multicenter study, results of 209 patients with 215 breast masses classified as BI-RADS 4a or 4b at US are reported. Patients were enrolled between 2015 and 2016. Masses were first evaluated with US with knowledge of previous clinical information and imaging results, and from this information a US imaging-based probability of malignancy (POM) and BI-RADS category were assigned to each mass. The same masses were then re-evaluated at OA/US. During the OA/US evaluation, radiologists scored five OA/US features, and then reassigned an OA/US-based POM and BI-RADS category for each mass. BI-RADS downgrade and upgrade percentages at OA/US were assessed by using a weighted sum of the five OA feature scores. Results At OA/US, 47.9% (57 of 119; 95% CI: 0.39, 0.57) of benign masses classified as BI-RADS 4a and 11.1% (three of 27; 95% CI: 0.03, 0.28) of masses classified as BI-RADS 4b were correctly downgraded to BI-RADS 3 or 2. Two of seven malignant masses classified as BI-RADS 4a at US were incorrectly downgraded, and one of 60 malignant masses classified as BI-RADS 4b at US was incorrectly downgraded for a total of 4.5% (three of 67; 95% CI: 0.01, 0.13) false-negative findings. Conclusion At OA/US, benign masses classified as BI-RADS 4a could be downgraded in BI-RADS category, which would potentially decrease biopsies negative for cancer and short-interval follow-up examinations, with the limitation that a few masses may be inappropriately downgraded.

A Pivotal Study of Optoacoustic Imaging to Diagnose Benign and Malignant Breast Masses: A New Evaluation Tool for Radiologists.

Purpose To compare the diagnostic utility of an investigational optoacoustic imaging device that fuses laser optical imaging (OA) with grayscale ultrasonography (US) to grayscale US alone in differentiating benign and malignant breast masses. Materials and Methods This prospective, 16-site study of 2105 women (study period: 12/21/2012 to 9/9/2015) compared Breast Imaging Reporting and Data System (BI-RADS) categories assigned by seven blinded independent readers to benign and malignant breast masses using OA/US versus US alone. BI-RADS 3, 4, or 5 masses assessed at diagnostic US with biopsy-proven histologic findings and BI-RADS 3 masses stable at 12 months were eligible. Independent readers reviewed US images obtained with the OA/US device, assigned a probability of malignancy (POM) and BI-RADS category, and locked results. The same independent readers then reviewed OA/US images, scored OA features, and assigned OA/US POM and a BI-RADS category. Specificity and sensitivity were calculated for US and OA/US. Benign and malignant mass upgrade and downgrade rates, positive and negative predictive values, and positive and negative likelihood ratios were compared. Results Of 2105 consented subjects with 2191 masses, 100 subjects (103 masses) were analyzed separately as a training population and excluded. An additional 202 subjects (210 masses) were excluded due to technical failures or incomplete imaging, 72 subjects (78 masses) due to protocol deviations, and 41 subjects (43 masses) due to high-risk histologic results. Of 1690 subjects with 1757 masses (1079 [61.4%] benign and 678 [38.6%] malignant masses), OA/US downgraded 40.8% (3078/7535) of benign mass reads, with a specificity of 43.0% (3242/7538, 99% confidence interval [CI]: 40.4%, 45.7%) for OA/US versus 28.1% (2120/7543, 99% CI: 25.8%, 30.5%) for the internal US of the OA/US device. OA/US exceeded US in specificity by 14.9% (P < .0001; 99% CI: 12.9, 16.9%). Sensitivity for biopsied malignant masses was 96.0% (4553/4745, 99% CI: 94.5%, 97.0%) for OA/US and 98.6% (4680/4746, 99% CI: 97.8%, 99.1%) for US (P < .0001). The negative likelihood ratio of 0.094 for OA/US indicates a negative examination can reduce a maximum US-assigned pretest probability of 17.8% (low BI-RADS 4B) to a posttest probability of 2% (BI-RADS 3). Conclusion OA/US increases the specificity of breast mass assessment compared with the device internal grayscale US alone. Online supplemental material is available for this article. © RSNA, 2017.

Digital Colposcopy With Dynamic Spectral Imaging for Detection of Cervical Intraepithelial Neoplasia 2+ in Low-Grade Referrals: The IMPROVE-COLPO Study.

OBJECTIVE: The aim of the study was to determine, in a wide "real-world" setting, whether digital colposcopy with adjunctive dynamic spectral imaging (DSI) mapping increases the detection of women with high-grade cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: A multicenter, two-arm, observational, cross-sectional study that recruited women 21 years and older, having colposcopy after a low-grade abnormality screening result. The prospective arm collected outcomes of digital colposcopy with DSI used for identifying biopsy sites at the colposcopists' discretion. The retrospective control arm (number of subjects matched 1:1 per colposcopist) collected outcomes of standard colposcopy. The primary outcome was histopathological detection of women with CIN 2+ by colposcopic biopsy. RESULTS: The study included 1,788 women in the retrospective and 1,857 in the prospective arm from 39 US community-based clinics. Subject characteristics were comparable. A total of 71.6% of the women in the retrospective and 71.5% in the prospective arm underwent biopsy. The average number of biopsies increased from 1.032 (retrospective) to 1.256 (prospective). The yield of CIN 2+ patients was 7.21% in the retrospective and 9.48% in the prospective arm, a 2.27% difference (95% confidence interval = 0.47%-4.07%, p = .014) and 31.4% relative increase. The yield of CIN 3+ patients was 2.07% in the retrospective and 3.23% in the prospective arm, a 1.16% (95% confidence interval = 0.12%-2.24%, p = .031) absolute difference and 56.1% relative increase. The false-positive rates for biopsied patients were comparable (64.43% vs 62.04%, p = .139). CONCLUSIONS: Digital colposcopy with the adjunctive DSI increased CIN 2+ and CIN 3+ detection in low-grade referrals compared with standard colposcopy, with a similar number of women undergoing biopsy.

Pivotal trial of an autonomous AI-based diagnostic system for detection of diabetic retinopathy in primary care offices.

Artificial Intelligence (AI) has long promised to increase healthcare affordability, quality and accessibility but FDA, until recently, had never authorized an autonomous AI diagnostic system. This pivotal trial of an AI system to detect diabetic retinopathy (DR) in people with diabetes enrolled 900 subjects, with no history of DR at primary care clinics, by comparing to Wisconsin Fundus Photograph Reading Center (FPRC) widefield stereoscopic photography and macular Optical Coherence Tomography (OCT), by FPRC certified photographers, and FPRC grading of Early Treatment Diabetic Retinopathy Study Severity Scale (ETDRS) and Diabetic Macular Edema (DME). More than mild DR (mtmDR) was defined as ETDRS level 35 or higher, and/or DME, in at least one eye. AI system operators underwent a standardized training protocol before study start. Median age was 59 years (range, 22-84 years); among participants, 47.5% of participants were male; 16.1% were Hispanic, 83.3% not Hispanic; 28.6% African American and 63.4% were not; 198 (23.8%) had mtmDR. The AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% (95% CI, 81.8-91.2%) (>85%), specificity of 90.7% (95% CI, 88.3-92.7%) (>82.5%), and imageability rate of 96.1% (95% CI, 94.6-97.3%), demonstrating AI's ability to bring specialty-level diagnostics to primary care settings. Based on these results, FDA authorized the system for use by health care providers to detect more than mild DR and diabetic macular edema, making it, the first FDA authorized autonomous AI diagnostic system in any field of medicine, with the potential to help prevent vision loss in thousands of people with diabetes annually. ClinicalTrials.gov NCT02963441.

Increased detection of precancerous cervical lesions with adjunctive dynamic spectral imaging.

OBJECTIVE: To validate, in US community-based colposcopy clinics, previous reports of increased detection of high-grade cervical intraepithelial neoplasia (CIN2+) with biopsies selected using dynamic spectral imaging (DSI) mapping after standard colposcopy. STUDY DESIGN: Cross-sectional observational study of 26 colposcopists across nine clinics recruiting consecutive colposcopy patients. Standard assessment with biopsy selections was completed before seeing the DSI map which was subsequently interpreted and used for additional biopsies per clinical judgment. Primary measure was the number of women with CIN2+ detected by DSI-assisted biopsies, over those detected by standard colposcopy biopsies. RESULTS: A total of 887 women were recruited. After exclusions, 881 women and 1,189 biopsies were analyzed. Standard biopsy detected 78 women with CIN2+ and DSI-assisted biopsies another 34, increasing the detection rate from 8.85% to 12.71% (p=0.00016). This was achieved with 16.16% of DSI-assisted biopsies finding CIN2+ compared to 13.24% for the preceding standard biopsies. For secondary specificity analysis, 431 women had only

A method for establishing class III medical device equivalence: sodium hyaluronate (GenVisc 850) for the treatment of knee osteoarthritis.

Although the concept of equivalence for drugs (generics) and biologics (biosimilars) has been readily adopted, the concept of equivalence or indistinguishable characteristics for class III medical devices has yet to be specifically addressed regarding a defined regulatory approval process in the US. In September 2015, GenVisc 850® (sodium hyaluronate), a hyaluronic acid approved for the treatment of knee osteoarthritis, was approved by the US Food and Drug Administration (FDA) based upon indistinguishable characteristics in comparison to an approved branded hyaluronic acid (Supartz®/Supartz FX™). The purpose of this paper is to review the methodology and report the main outcomes used to demonstrate clinical comparability of GenVisc 850 with Supartz/Supartz FX. The FDA approval was collectively attained using prospectively defined methods for preclinical, physical, and chemical testing, as well as noninferiority in clinical performance comparisons. Evidence from five randomized controlled studies of Supartz/Supartz FX vs saline control injections (used for Supartz approval), two randomized controlled trials of GenVisc 850 vs saline control injections, and one randomized controlled study of GenVisc 850 vs Supartz/Supartz FX provided evidence of safety for GenVisc 850. Efficacy was further assessed based on assessment of the same Supartz studies and three prospectively identified GenVisc 850 studies. A Bayesian network meta-analysis was used to demonstrate that the clinical efficacy of GenVisc 850 was noninferior to Supartz/Supartz FX and superior to saline control. Overall, safety of GenVisc 850 was similar to that of Supartz/Supartz FX and saline control injections, while efficacy of GenVisc 850 was noninferior to that of Supartz/Supartz FX and superior to saline control injections.

Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial.

AIMS: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies. METHODS AND RESULTS: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population. CONCLUSION: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population.

A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.

Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin-angiotensin-aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12-0.3 g, 24-3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium.

Sodium zirconium cyclosilicate in hyperkalemia.

BACKGROUND: Hyperkalemia (serum potassium level, >5.0 mmol per liter) is associated with increased mortality among patients with heart failure, chronic kidney disease, or diabetes. We investigated whether sodium zirconium cyclosilicate (ZS-9), a novel selective cation exchanger, could lower serum potassium levels in patients with hyperkalemia. METHODS: In this multicenter, two-stage, double-blind, phase 3 trial, we randomly assigned 753 patients with hyperkalemia to receive either ZS-9 (at a dose of 1.25 g, 2.5 g, 5 g, or 10 g) or placebo three times daily for 48 hours. Patients with normokalemia (serum potassium level, 3.5 to 4.9 mmol per liter) at 48 hours were randomly assigned to receive either ZS-9 or placebo once daily on days 3 to 14 (maintenance phase). The primary end point was the exponential rate of change in the mean serum potassium level at 48 hours. RESULTS: At 48 hours, the mean serum potassium level had decreased from 5.3 mmol per liter at baseline to 4.9 mmol per liter in the group of patients who received 2.5 g of ZS-9, 4.8 mmol per liter in the 5-g group, and 4.6 mmol per liter in the 10-g group, for mean reductions of 0.5, 0.5, and 0.7 mmol per liter, respectively (P<0.001 for all comparisons) and to 5.1 mmol per liter in the 1.25-g group and the placebo group (mean reduction, 0.3 mmol per liter). In patients who received 5 g of ZS-9 and those who received 10 g of ZS-9, serum potassium levels were maintained at 4.7 mmol per liter and 4.5 mmol per liter, respectively, during the maintenance phase, as compared with a level of more than 5.0 mmol per liter in the placebo group (P<0.01 for all comparisons). Rates of adverse events were similar in the ZS-9 group and the placebo group (12.9% and 10.8%, respectively, in the initial phase; 25.1% and 24.5%, respectively, in the maintenance phase). Diarrhea was the most common complication in the two study groups. CONCLUSIONS: Patients with hyperkalemia who received ZS-9, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy. (Funded by ZS Pharma; ClinicalTrials.gov number, NCT01737697.).